Radial glial cells play a critical role in the construction of the mammalian brain, initially, by functioning as a source of new neurons and by providing a permissive and instructive scaffold for neuronal migration, and eventually, by contributing to the formation of astroglial cell lineages in the mature brain. The function of radial glia depends on the structural and molecular polarity of these cells. Abnormalities in radial glial development, differentiation, and neuron- radial glial interactions lead to aberrant placement and connectivity of neurons in the human brain, an underlying cause of many developmental brain disorders such as epilepsy and schizophrenia, as well as of gross malformations such as microencephaly (small brain), schizencephaly (split brain hemispheres), lissencephaly (smooth cerebrum, without convolutions), macrogyria (large convolutions), polymicrogyria (small cerebral convolutions), and tuberous sclerosis. The aim of this proposal is to elucidate the molecular mechanisms that determine how radial glial cells differentiate to function as neuronal precursors, neuronal migratory guides, and as astrocyte precursors during cerebral cortical development. To examine the molecular signals regulating these processes, we have focused on neuregulin l (NRG1) and its receptors (erbB2, 3, and 4). Our earlier findings demonstrate that that NRG1 and its receptors play a crucial role in radial glial cell function in the developing cerebral cortex (Schmid et al., 2003). NRG1 promotes the establishment and differentiation of radial glia. In the absence of NRG1 signaling via erbB2 receptors, radial glial polarity and development is abnormal. Recently, NRG1 has been identified as a susceptibility gene for schizophrenia (Stefansson et al., 2002a; Stefansson et al., 2002b). Based on these findings, we hypothesize that the NRG1/erbB signaling plays an instructive role in radial glial cell development and differentiation. The proposed studies will test this hypothesis by analyzing (1) the role of NRGl-erbB2 interactions in the differentiation, polarity, and function of radial glial cells in cerebral cortex, and (2) whether radial glial identity can be regained in postnatal cerebral cortex through changes in NRG1- erbB2 signaling system. Together, these studies on radial glial development and differentiation will help in deciphering the basic mechanisms guiding normal cerebral cortical development as well as in unveiling the pathogenesis of various developmental brain disorders, including schizophrenia, where abnormal radial glial development and differentiation may result in defective cerebral cortical organization and thus in neurological functional deficits.